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Antipsychotic agents

Antipsychotic agents . By S.Bohlooli PhD School of Medicine, Ardabil University of Medical Sciences. Introduction.

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Antipsychotic agents

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  1. Antipsychotic agents By S.BohlooliPhD School of Medicine, Ardabil University of Medical Sciences

  2. Introduction • Neuroleptic: synonym for antipsychotic drug; originally indicated drug with antipsychotic efficacy but also neurologic (extrapyramidal motor) side effects, now claimed as subtype of antipsychotic drugs • Typical neuroleptic: older agents fitting this description • atypical" antipsychotic : newer agents: antipsychotic efficacy with reduced or no neurologic side effects

  3. History • Reserpine • Chlorpromazine: neuroleptic agent • The discovery of clozapine was in 1959 • antipsychotic drugs need not cause EPS

  4. Nature of Psychosis & Schizophrenia The presence of delusions (false beliefs) Various types of hallucinations, usually auditory or visual, but sometimes tactile or olfactory Disorganized thinking in a clear sensorium

  5. The Serotonin Hypothesis of Schizophrenia Hallucinogens such as LSD (lysergic acid diethylamide) and mescaline are serotonin (5-HT) agonists 5-HT2A-receptor blockade is a key factor in the mechanism of action of the main class of atypical antipsychotic drugs such as clozapine and quetiapine. 5-HT2C-receptor stimulation provides a further means of modulating

  6. The Dopamine Hypothesis of Schizophrenia • Was the first neurotransmitter-based concept • Excessive limbic dopaminergic activity plays a role in psychosis • Many antipsychotic drugs strongly block postsynaptic D2receptors: • Includes partial dopamine agonists, such as aripiprazole and bifeprunox • Drugs that increase dopaminergic activity either aggravate schizophrenia psychosis or produce psychosis de novo • Dopamine-receptor density is high postmortem • The atypical antipsychotic drugs • Much less effect on D2receptors • Role of other dopamine receptors and to nondopaminereceptors

  7. The Glutamate Hypothesis of Schizophrenia Glutamate is the major excitatory neurotransmitter in the brain Phencyclidine and ketamine are noncompetitive inhibitors of the NMDA receptor Hypofunctionof NMDA receptors, located on GABAergic interneurons

  8. Basic Pharmacology of Antipsychotic Agents

  9. Chemical Types

  10. Chemical Types

  11. Chemical Types

  12. Antipsychotic Drugs: Relation of Chemical Structure to Potency and Toxicities

  13. Pharmacokinetics • Absorption and Distribution • Readily but incompletely absorbed • Significant first-pass metabolism • Highly lipid-soluble and protein-bound • Metabolism • Almost completely metabolized • Drug-drug interactions should be considered

  14. Pharmacodynamics

  15. KEY CONCEPTS: • All neuroleptics are equally effective in treating psychoses, including schizophrenia, but differ in their tolerability. • All neuroleptics • block one or more types of DOPAMINE receptor, but differ in their other neurochemical effects. • show a significant delay before they become effective. • produce significant adverse effects.

  16. GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS The older, typical neuroleptics are effective antipsychotic agents with neurologic side effects involving the extrapyramidal motor system. Typical neuroleptics block the dopamine-2 receptor.

  17. GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS • Typical neuroleptics do not produce a general depression of the CNS, e.g. respiratory depression • Abuse, addiction, physical dependence do not develop to typical neuroleptics.

  18. GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS Typical neuroleptics are generally more effective against positive (active) symptoms of schizophrenia than the negative (passive) symptoms.

  19. Positive/active symptoms include thought disturbances, delusions, hallucinations Negative/passive symptoms include social withdrawal, loss of drive, diminished affect, paucity of speech, impaired personal hygiene

  20. THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS All appear equally effective; choice usually based on tolerability of side effects Most common are haloperidol ,chlorpromazine and thioridazine Latency to beneficial effects; 4-6 week delay until full response is common 70-80% of patients respond, but 30-40% show only partial response

  21. THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS (Continued) Relapse, recurrence of symptoms is common ( approx. 50% within two years). Noncompliance is common. Adverse effects are common.

  22. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS • Anticholinergic (antimuscarinic) side effects: • Dry mouth, blurred vision, tachycardia, constipation, urinary retention, impotence • Antiadrenergic (Alpha-1) side effects: • Orthostatic hypotension , reflex tachycardia • Sedation • Antihistamine effect: sedation, weight gain

  23. KEY CONCEPT: DOPAMINE-2 RECEPTOR BLOCKADE IN THE BASAL GANGLIA RESULTS IN EXTRAPYRAMIDAL MOTOR SIDE EFFECTS (EPS). DYSTONIA NEUROLEPTIC MALIGNANT SYNDROME PARKINSONISM TARDIVE DYSKINESIA AKATHISIA

  24. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued) Increased prolactin secretion (common with all; from dopamine blockade) Weight gain (common, antihistamine effect?) Photosensitivity (v. common w/ phenothiazines) Lowered seizure threshold (common with all) Leukopenia , agranulocytosis (rare; w/ phenothiazines) Retinal pigmentopathy (rare; w/ phenothiazines)

  25. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued) Chlorpromazine and thioridazine produce marked autonomic side effects and sedation; EPS tend to be weak (thioridazine) or moderate (chlorpromazine). Haloperidol, thiothixene and fluphenazine produce weak autonomic and sedative effects, but EPS are marked.

  26. MECHANISMS OF ACTION OF TYPICAL NEUROLEPTICS and Some Side Effects DOPAMINE-2 receptor blockade in meso-limbic and meso-cortical systems for antipsychotic effect. DOPAMINE-2 receptor blockade in basal ganglia (nigro-striatal system) for EPS DOPAMINE-2 receptor supersensitivity in nigrostriatal system for tardivedyskinesia

  27. LONG TERM EFFECTS OF D2 RECEPTOR BLOCKADE: Dopamine neurons reduce activity. Postsynaptic D-2 receptor numbers increase (compensatory response). When D2 blockade is reduced, DA neurons resume firing and stimulate increased # of receptors >> hyper-dopamine state >> tardive dyskinesia

  28. MANAGEMENT OF EPS Dystonia and parkinsonism: anticholinergic antiparkinsondrugs Neuroleptic malignant syndrome: muscle relaxants, DA agonists, supportive Akathisia: benzodiazepines, propranolol Tardivedyskinesia: increase neuroleptic dose; switch to clozapine

  29. ADDITIONAL CLINICAL USES OF TYPICAL NEUROLEPTICS • Adjunctive in acute manic episode • Tourette’s syndrome (Haloperidole ) • Control of psychosis in depressed patient • Phenothiazines are effective anti-emetics, • Esp. prochlorperazine • Also, anti-migraine effect

  30. Differences among Antipsychotic Drugs Chlorpromazine: 1 = 5-HT2A > D2 > D1 Haloperidol: D2 > 1 > D4 > 5-HT2A > D1 > H1 Clozapine: D4 = 1 > 5-HT2A > D2 = D1 Olanzapine: 5-HT2A > H1 > D4 > D2 >1 > D1 Aripiprazole: D2 = 5-HT2A > D4 > 1 = H1 >> D1 Quetiapine: H1 > 1 > M1,3 > D2 > 5-HT2A

  31. GENERAL CHARACTERISTICS OF ATYPICAL Antipsychotic Effective antipsychotic agents with greatly reduced or absent EPS, esp. reduced Parkinsonism and tardive dyskinesia All atypical neuroleptics block dopamine and serotonin receptors; other neurochemical effects differ Are effective against positive and negative symptoms of schizophrenia; and in patients refractory to typical neuroleptics

  32. HYPOTHESIZED MECHANISMS OF ACTION OF ATYPICAL NEUROLEPTICS • Combination of Dopamine-4 and Serotonin-2 receptor blockade in cortical and limbic areas for the “pines” like clozapine • Combination of Dopamine-2 and Serotonin-2 receptor blockade (esp. risperidone)

  33. PHARMACOLOGY OF CLOZAPINE FDA-approved for patients not responding to other agents or with severe tardivedyskinesia Effective against negative symptoms Also effective in bipolar disorder Little or no parkinsonism, tardivedyskinesia, PRL elevation, neuro-malignant syndrome; some akathisia

  34. PHARMACOLOGY OF CLOZAPINE (Continued ) • Other adverse effects; • Weight gain • Increased salivation • Increased risk of seizures • Risk of agranulocytosis requires continual monitoring

  35. PHARMACOLOGY OF OLANZAPINE • Olanzapine is clozapine without the agranulocytosis. • Same therapeutic effectiveness • Same side effect profile

  36. PHARMACOLOGY OF QUETIAPINE • Quetiapine is olanzapine without the anticholinergic effects. • Same therapeutic effectiveness • Same side effect profile

  37. Resperidone • Highly effective against positive and negative symptoms • Adverse effects: • EPS incidence is dose-related • Alpha-1 receptor blockade • Little or no anticholinergic or antihistamine effects • Weight gain, PRL elevation

  38. Adverse Pharmacologic Effects of Antipsychotic Drugs

  39. General Therapeutic Principles for Use of Neuroleptics in Schizophrenia(NIH Consensus Statement, 1999) • Use typical for: • 1st acute episode w/ + or +/- symptoms • Switch to atypical if: • Breakthrough after Rx w/ typical • Use typical (depot prep) when: • Patient is noncompliant

  40. General Therapeutic Principles for Use of Neuroleptics in Schizophrenia • If response is inadequate to: • Typical; switch to Atypical • Atypical; raise dose or switch to another Atypical • Typical and Atypical; switch to clozapine ® • For maintenance, lifetime Rx is required.

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